Anyone Taking Rapamycin Monthly?

[LaraPo]

What is AUC? Thanks.

[Barnabas]

AUC is area under the curve.

Suppose you have time on the x axis and speed on the y axis. Area under the curve would be the amount of distance traveled during that time.

[EenDwaze]

In the past, l have tried 8 mg weekly and then every 2 weeks for a total of 4 months. During that time, my healing rate slowed noticeably and l got sick at a much higher frequency. I’m currently doing 4 mg every 3 weeks(only 5 weeks in). My theory is l am slow metabolizer, assuming 85 hour half life and shooting for 5.5 half lives.

[Herm]

At the end of 4 months, just prior to the time where you would have taken the next dose of 8 mg (with 15% bioavailability and biweekly dosing), approximately 1.284 mg of the drug would be present in your body just prior to the next dose. (85 hour half-life)

At the end of the same 4 month period with dosing 4 mg every three weeks, 15% bioavailability, same half-life, at the end of 4 months, just prior to the time where the next dose of 4 mg would be given (with 15% bioavailability), approximately 0.610 mg of the drug would have accumulated in the body.

Congratulations! You came up with a dosing regimen that leaves almost exactly 50% of the drug in your body before the next dose of drug compared to the previous dosing regimen. I hope that works out for you abolishing the toxicity you noticed.

I went through a similar routine to arrive at my current dose of 3 mg every three weeks, assuming a half-life of 67 hours and 15% bioavailability. Of course, the assumptions for the PK equations are a particular half-life and a particular % bioavailability.

[EenDwaze]

How many experiments did you try before you landed at this dosing schedule?

[Herm]

@Herm

It has taken me about a year to get to a reasonable dose of rapamycin without discernible side effects. I started on rapamycin about a year and a half ago. 1mg/week. After a month I experienced an extremely painful aphthous ulcer. I stopped rapamycin until it fully cleared, which took almost a month, highly unusual for stomatitis. I restarted rapamycin 1 mg every two weeks. Good for three months, same event as above, same place. Waited a few weeks to clear, and restarted rapamycin at 1 mg every three weeks. No problems, so about three months ago I upped the dose to 2 mg, but not the frequency, which is still every three weeks. … If good - up the dose to 3 mg every three weeks, and go back down in dose if any aphthous ulcers, or other events possibly related to rapamycin emerge.

I’ll be taking my second cycle of 3 mg every three weeks on July 4, and if all good for a couple more cycles, I’ll up to 4 mg every three weeks…

[KarlT]

@Herm im not following your math. 3 weeks is a lot of half lives to still have a significant amount of drug in your body?

[Herm]

Actually you followed the math better than I since I calculated the amount in the body after, not before the nth dose at steady state. So the accumulation is 0.084 mg and 0.010 mg respectively present before the next dose and 1.284 mg and 0.610 mg right after the next dose.

[John_Hemming]

@Herm and I are I think the only two people on this forum who have gone for dosing every 21 days.

What I think really matters, however, is not the level of rapamycin when the next dose is taken, but the proportion of time that rapamycin is too low to have a material effect.

I take a higher dose of 6mg (Zydus or Biocon) with pomegranate, pomelo or grapefruit.

[Herm]

@John_Hemming I agree, based on my interpretation of the animal literature. I would posit that benefits accrue proportional to the Cmax, the highest concentration that occurs after oral dosing, while the adverse events are related to the amount of time the blood concentration remains above some undefined concentration, with a lot of individual variance. Compounds found in GFJ, discussed in this forum, increase AUC (exposure) 350% implying up to a 3.5 x increase in half-life, which is quite a lot. If you started with a 67 hour half-life, now it would be 234.5 hours, which is a little over a week of 168 hours, hence the accumulation. Quadruple checked the math thanks to @KarlT and this implies 1.75 mg of rapamycin are in the body before the next dose if 6 mg were absorbed and 0.163 mg if 15 % was absorbed. Actually you may absorb even more given decrease of rapamycin clearance as GFJ inhibits intestinal CYP3A4.

[RobTuck]

Can you guys who have been taking and experimenting with rapa longer identify the ideal blood level profile? Is it to achieve the highest Cmax (if so, how high) followed by the shortest (or the longest) right tail? And how is this goal modulated by GFJ and other CYP3A4 inhibitors? If I understand GFJ correctly, it seems like a free lunch in that it increases Cmax and lengthens the tail of decline, if that is the goal). Quercetin seems to have a different impact.

Practically speaking, I have been under the impression that I wanted to do a little “house cleaning” and then return my immune system to its former state as quickly as possible. I spend a lot of time in the sun, for example, and do not want to have to avoid it for days on end. This last week, I took 4 mg. with sardines and no CYP3A4 inhibitors other than the fact that a small amount of quercetin is part of my daily supplement stack. I don’t know if this is a good or bad strategy because I’m unclear on the agreed upon goal, other things being equal.

[blsm]

I’m currently doing 3mg every 21 days/3 weeks as well. It seems the the sweet spot for maintaining the benefits and works well around my time spent in high risk of infection exposure on the job.

[KarlT]

I’m gonna follow the smart guys in the room and try 3 weeks. Just gotta work out a dose.

@John_Hemming Have you noticed in difference due to what type of fruit you’re using?

[Herm]

Restating the question, is it better to have more constant but lower blood levels, or pulse dosing to achieve beneficial effects? And how does this change the adverse event profile? As an example, 1mg/day. or a pulse dose of 7 mg / week. Both of these doses result in the same exposure. If anyone knows of a comparative study, even a short one looking at some surrogate biomarkers of inflammation and related to an"on target" effect of rapamycin I would be interested in hearing about them. At this point, I don’t think we know which dose regimen gives the best risk to benefit. So I digress to biochemical philosophy.

Mark Mattson has done some amazing work in the nutritional impact of diet on ageing. One concept which has intrigued mefor a long time is the concept of [hormesis] (https://journals.sagepub.com/doi/pdf/10.1177/0960327107083417) that is, beneficial effects of low levels of stress. Caloric restriction is a form of cellular stress. Rapamycin has effects that biochemically mimic caloric restriction. Fasting has beneficial effects, but obviously at some point, you have to eat to survive. So my hypothesis is that pulse dosing with rapamycin, a mimic of fasting over the period of time when blood levels are higher than some unknown concentration may also confer similar benefits, but also allow between dose recovery back to a homeostatic state. A dosing regimen that maintains the blood level above that unknown concentration over the dosing period, weeks, months, etc. may not be as beneficial, much like fasting over a very long period of time. Decreased protein synthesis, increased protein catabolism, changes in lipid metabolism, immune effects, etc.common to both long term fasting and continuous rapamycin exposure. But it is just a hypothesis, but one on which I will take a gamble until I become aware of more data.

[Herm]

Regarding GFJ and friends, the phytochemicals present decrease intestinal and liver CYP3A4 thereby increasing the fraction of dose absorbed, and decrease clearance thereby increasing half life. The increase in fraction absorbed is frugal as it is analogous to taking more rapamycin which is more expensive than GFJ,but the decrease in clearance and extension of half-life may or may not be beneficial depending on how much the clearance decreases (or half life increases). For me it would be nice to have a compound that increases fraction absorbed, decreasing the adverse events to the wallet and bank account, but has much less effect on total clearance, but such is not been found as far as I know.

[John_Hemming]

Other than the fact that I prefer the taste of Pomegranate, no.

[Olafurpall]

@Herm

Compounds found in GFJ, discussed in this forum, increase AUC (exposure) 350% implying up to a 3.5 x increase in half-life, which is quite a lot. If you started with a 67 hour half-life, now it would be 234.5 hours, which is a little over a week of 168 hours, hence the accumulation.

That’s not correct. GFJ increases the amount of rapamycin that gets absorbed. It does not change the half-life of the rapamycin in the blood. The half life is still the same as before.

[John_Hemming]

Although I agree with @Olafurpall that the change in the amount absorbed will not itself change the half life, I think it is possible to extend the half life by knocking out enzymes in the liver.

However, this is not something I would try to do as I aim to keep Rapamycin effectively inactive for most of the time.

[Olafurpall]

I agree. For most purposes, trying to increase the half-life would be a bad idea. It’s already long enough for the type of intermittent inhibition that is likely best for longevity.

[cl-user]

GFJ adds a lot of variability to the pharmacokinetics of rapamycin (and other drugs).

Here are some quotes from papers on pubmed about that:

Grapefruit juice can both increase the absorption and decrease the clearance of rapamycin by inhibiting CYP3A4 enzymes and P-gp transporters. This dual effect means that the drug not only enters the bloodstream in higher concentrations but also remains in the body for a longer duration, thereby increasing its half-life.

grapefruit juice predominantly inhibits intestinal CYP3A4 and to a lesser extent hepatic CYP3A4

and from Phase 1 Studies of Sirolimus Alone or in Combination with Pharmacokinetic Modulators in Advanced Cancer Patients

With GFJ, the AUC is 3x to 5x greater and the half-life is 1.3x to 2x longer which is quite a lot.

grapefruit juice is a potent inhibitor of intestinal CYP3A4, CYP1A2, and CYP2A6 (27). In fact, small bowel enterocyte CYP3A4 protein levels begin to decrease within hours of grapefruit juice administration and the effect is maximal if grapefruit juice is ingested simultaneously or within the previous four hours of drug administration. Furthermore, the half-life of the effect is approximately 12 hours and enzyme levels are reduced by a mean of 62% even after 5 days of grapefruit juice consumption (21). The reduction in protein level is likely post-transcriptional requiring de novo CYP3A4 synthesis (27). Although the magnitude of the interaction is highly variable, it is reproducible within individuals and seems to be dependent on small bowel CYP3A4 content, i.e. persons with the highest intestinal CYP3A4 content have the largest reduction in enzyme levels and subsequently the greatest effect on drug metabolism (27–30).

Interestingly, different grapefruit juice formulations appear to vary in inhibitory potency

In summary GFJ increases Cmax, AUC and half-life with a lot of variability on the individual and GF used. BTW Max is irrelevant but not the others.

People using GFJ should really measure their own blood concentration at 48 and 72h to assess the level and half-life.